This invention deals with a synthetic design of drug-incorporated novel dendrimers for quantitatively controlled drug delivery.
Dendrimers are well known in the art and there are multiple patents, treatises, and textbooks on their preparation and use.
Dendrimers have unique cascade structures with multiple functional termini. The multifunctional surface of dendrimers makes them easy to chemically conjugate with other molecules, such as drugs, for targeted delivery and controlled release of the drugs. Up to now, little attention has been paid to utilizing the cascade feature of dendrimer structures for controlled-release of drugs. This invention takes advantage of this distinct feature to develop an ideal drug delivery system since each layer of the structure can be tailored with a certain amount of drug entities that are well defined by the dendrimer structure.
Under proper physiological conditions, the dendritic drug can be degraded naturally or digested by enzymes to release the drugs sequentially and quantitatively layer by layer. The drugs on the surface, or exterior of the dendrimer, are released first, and then the interior drug units begin to be liberated when all of the periphery drug units have left. The drug units at the core of the dendrimer will be released last. Thus, a well-controlled quantitative delivery of the drug can be approached through this dendritic design.
At the current time, there are two known methods for utilizing dendrimers in drug delivery, dendrimer drug conjugation and dendrimer drug encapsulation. In the conjugation method, a drug is attached to the surface of the carrier molecule, i.e. the dendrimer, and the encapsulation method utilizes the dendritic voids to accommodate the drug molecules for improving the drug properties such as solubility and toxicity in therapeutic treatment.
However, both methods have limitations in drug controlled release and targeted delivery. For example, in the dendrimer, the conjugated drugs are only located on the surface of the dendrimer and they all can be easily released at the same time. Therefore, the drug-controlled release will be obviously limited in this system. The encapsulation of drugs with dendrimers is rather unstable for in vivo applications since the drugs are just physically entrapped inside the dendritic voids and the leakage of the drug can be a big issue during the delivery.
Examples of U.S. Patents and publications that deal with dendrimer drug encapsulation, dendrimer drug conjugation and alternative drug delivery systems are: U.S. Pat. No. 6,756,037 to Greenwald et al.; U.S. Pat. No. 6,838,528 to Zhao; U.S. Pat. No. 6,942,877 to Vogt, et al.; U.S. Pat. No. 6,913,760 to Carr, et al.; U.S. Pat. No. 6,681,068 to Ng, et al.; U.S. Pat. No. 6,576,222 to Platzek, et al.; U.S. Pat. No. 5,945,100 to Fick; U.S. Pat. No. 6,864,350 to Harris; U.S. Pat. No. 6,790,437 to Malik, et al.; U.S. Pat. No. 6,706,892 to Eziin, et al.; U.S. Pat. No. 6,623,729 to Park et al.; U.S. Pat. No. 6,475,495 to Maignan; U.S. Pat. No. 6,458,347 to Sugawara, et al.; U.S. Pat. No. 6,432,423 to Maignan; U.S. Pat. No. 6,296,842 to Jaworowicz, et al.; U.S. Pat. No. 6,623,764 to Sokoll, et al.; U.S. Pat. No. 6,623,730 to Williams, et al.; U.S. Pat. No. 6,600,010 to Mao, et al.; U.S. Pat. No. 6,280,745 to Flore, et al.; U.S. Pat. No. 5,965,119 to Greenwald, et al.; U.S. Pat. No. 6,861,066 to Van de Casteele; U.S. Patent publication 2005/0169882 A1 to Lowe, et al.; U.S. Patent publication 2005/0147688 A1 to Van de Casteele; U.S. Patent publication 2005/0147681 A1 to Zhao; U.S. Patent publication 2005/0119450 A1 to Wang, et al.; U.S. patent publication 2005/0112088 A1 to Zhao, et al.; U.S. Patent publication 2005/0042753 A1 to Yang, et al.; U.S. Patent publication 2005/0037075 A1 to Farokhzad, et al.; U.S. Patent publication 2005/0036973 A1 to Sato, et al.; U.S. publication 2005/0025820 A1 to Kester, et al.; U.S. Patent publication 2005/0019923 A1 to Uchegbu, et al.; U.S. Patent publication 2004/0247680 A1 to Farokhzad, et al.; U.S. Patent publication 2004/0228831 A1 to Belinka, et al.; U.S. Patent publication 2004/0161403 A1 to Zhao, et al.; U.S. Patent publication 2004/0151689 to Majoros, et al.; U.S. Patent publication 2004/0142475 A1 to Barman, et al.; U.S. Patent publication 2004/0028745 A1 to Bouhadir, et al.; U.S. Patent publication 2003/0232968 A1 to Li, et al.; U.S. Patent 2003/0232929 A1 to Huang, et al.; U.S. Patent publication 2003/0219785 A1 to Hallahan, et al.; U.S. Patent publication 2003/0190364 A1 to Panitch, et al.; U.S. Patent publication 2003/0181619 A1 to Matyjaszewski et al.; U.S. Patent publication 2003/0175209 A1 to Mueller, et al.; U.S. Patent publication 2003/0170311 A1 to Van de Casteele; U.S. Patent publication 2003/0147812 A1 to Ueberle; U.S. Patent publication 2003/0133972 A1 to Danthi, et al.; U.S. Patent publication 2003/0129223 A1 to Wartchow, et al.; U.S. Patent publication 2003/0083286 A1 to Teng, et al.; U.S. Patent publication 2003/0082103 A1 to Wartchow, et al.; U.S. Patent Publication 2003/0077295 A1 to Malik, et al.; U.S. Patent publication 2003/0073852 A1 to Ng, et al.; U.S. Patent publication 2003/0068379 A1 to Li, et al.; U.S. Patent publication 2003/0064984 A1 to Ng, et al.; U.S. Patent publication 2003/0064050 A1 to Malik, et al. U.S. Patent publication 2003/0059461 A1 to Backer, et al.; U.S. Patent publication 2003/0050426 A1 to Shastri; U.S. Patent publication 2002/0192843 A1 to Kaganove, et al.; U.S. Patent publication 2002/0165179 A1 to Baker; U.S. Patent publication 2002/0164648 A1 to Goins, et al.; U.S. Patent publication 2002/0156047 A1 to Zhao; U.S. Patent publication 2002/0151004 A1 to Craig; U.S. Patent publication 2002/0123609 A1 to Frechet, et al.; U.S. Patent publication 2002/0071843 A1 to Li, et al.; U.S. Patent publication 2002/0045263 A1 to Leong, et al.; U.S. Patent publication 2002/0022012 A1 to Cooper, et al.; U.S. Patent publication 2002/0000681 A1 to Gupta, et al.; U.S. Patent publication 2001/0011109 A1 to Balogh, et al., and U.S. Patent publication 2001/0007666 A1 to Hoffman, et al.
Linear polymeric drugs have been discovered for drug delivery applications. For example in U.S. Pat. No. 6,613,807, that issued on Sep. 2, 2003 and U.S. Pat. No. 6,468,519 that issued on Oct. 22, 2002, both to Uhrich, there is disclosed therapeutic polyanhydride compounds for drug delivery. Uhrich also discloses linear drugs in U.S. Pat. No. 6,689,350, that are based on therapeutic polyesters and polyamides.
The linear drugs dissociate into free drug units under certain critical conditions, leading to the sudden release of the drug. Thus, the control of the drug delivery for linear drugs is not well controlled and the drug release is not quantitative.
The dendritic drugs of this invention have better control and thus a quantitative drug release can be obtained. There is no prior art relating to drugs that control release both sequentially and quantitatively like the dendritic drugs of this invention.